Cartridge systems, capacitive pumps and multi-throw valves and pump-valve systems and applications of same

ABSTRACT

In one aspect of the invention, the fluidic device includes a fluidic chip includes a body having a first surface and an opposite, second surface, one or more channels formed in the body in fluidic communications with input ports and output ports for transferring one or more fluids between the input ports and the output ports, and a fluidic chip registration means formed on the first surface for aligning the fluidic chip with a support structure; and an actuator configured to engage with the one or more channels at the second surface of the body for selectively and individually transferring the one or more fluids through the one or more channels from at least one of the input ports to at least one of the output ports at desired flowrates.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalPatent Application Ser. Nos. 62/719,868, and 62/868,303, filed Aug. 20,2018 and Jun. 28, 2019, respectively.

This application is also a continuation-in-part application of U.S.patent application Ser. No. 15/820,506, filed Nov. 22, 2017, nowallowed, which is a divisional application of U.S. patent applicationSer. No. 13/877,925, filed Jul. 16, 2013, now abandoned, which is anational stage entry of PCT Application Serial No. PCT/US2011/055432,filed Oct. 7, 2011, which claims priority to and the benefit of, U.S.Provisional Patent Application Ser. No. 61/390,982, filed Oct. 7, 2010.

This application is also a continuation-in-part application of U.S.patent application Ser. No. 16/049,025, filed Jul. 30, 2018, which is acontinuation application of U.S. patent application Ser. No. 14/363,074,filed Jun. 5, 2014, now U.S. Pat. No. 10,078,075, is a national stageentry of PCT Application Serial No. PCT/US2012/068771, filed Dec. 10,2012, which claims priority to and the benefit of U.S. ProvisionalPatent Application Ser. Nos. No. 61/569,145, 61/697,204 and 61/717,441,filed Dec. 9, 2011, Sep. 5, 2012 and Oct. 23, 2012, respectively.

This application is also a continuation-in-part application of U.S.patent application Ser. No. 16/012,900, filed Jun. 20, 2018, which is adivisional application of U.S. patent application Ser. No. 15/191,092(the '092 application), filed Jun. 23, 2016, now U.S. Pat. No.10,023,832, which claims priority to and the benefit of U.S. ProvisionalPatent Application Ser. Nos. 62/183,571, 62/193,029, 62/276,047 and62/295,306, filed Jun. 23, 2015, Jul. 15, 2015, Jan. 7, 2016 and Feb.15, 2016, respectively. The '092 application is also acontinuation-in-part application of U.S. patent application Ser. Nos.13/877,925, 14/363,074, 14/646,300 (the '300 application) and Ser. No.14/651,174 (the '174 application), filed Jul. 16, 2013, Jun. 5, 2014,May 20, 2015 and Jun. 10, 2015, respectively. The '300 application, nowU.S. Pat. No. 9,874,285, is a national stage entry of PCT ApplicationSerial No. PCT/US2013/071026, filed Nov. 20, 2013, which claims priorityto and the benefit of U.S. Provisional Patent Application Ser. Nos.61/729,149, 61/808,455, and 61/822,081, filed Nov. 21, 2012, Apr. 4,2013 and May 10, 2013, respectively. The '174 application, now U.S. Pat.No. 9,618,129, is a national stage entry of PCT Application Serial No.PCT/US2013/071324, filed Nov. 21, 2013, which claims priority to and thebenefit of U.S. Provisional Patent Application Ser. Nos. 61/808,455 and61/822,081, filed Apr. 4, 2013 and May 10, 2013, respectively.

This application is also a continuation-in-part application of U.S.patent application Ser. No. 16/511,379, filed Jul. 15, 2019, which is adivisional application of U.S. patent application Ser. No. 15/776,524,filed May 16, 2018, now allowed, which is a national stage entry of PCTApplication Serial No. PCT/US2016/063586 (the '586 application), filedNov. 23, 2016, which claims priority to and the benefit of, U.S.Provisional Patent Application Ser. No. 62/259,327, filed Nov. 24, 2015.The '586 application is also a continuation-in-part application of U.S.patent application Ser. Nos. 13/877,925, 14/363,074, 14/646,300,14/651,174 and 15/191,092, filed Jul. 16, 2013, Jun. 5, 2014, May 20,2015, Jun. 10, 2015 and Jun. 23, 2016, respectively.

This application is also a continuation-in-part application of PCTPatent Application Serial No. PCT/US2019/034285 (the '285 application),filed May 29, 2019, which claims priority to and the benefit of U.S.Provisional Patent Application Ser. No. 62/677,468, filed May 29, 2018.The '285 application is also a continuation-in-part application of U.S.patent application Ser. Nos. 15/776,524 and 16/012,900, filed May 16,2018 and Jun. 20, 2018, respectively.

Each of the above-identified applications is incorporated herein byreference in its entirety.

Some references, which may include patents, patent applications, andvarious publications, are cited and discussed in the description of theinvention. The citation and/or discussion of such references is providedmerely to clarify the description of the invention and is not anadmission that any such reference is “prior art” to the inventiondescribed herein. All references cited and discussed in thisspecification are incorporated herein by reference in their entiretiesand to the same extent as if each reference was individuallyincorporated by reference.

STATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH

This invention was made with government support under Grant Nos.5UG3TR002097-02, U01CA202229 and HHSN271201700044C awarded by theNational Institutes of Health, Grant No. 83573601 awarded by the U. S.Environmental Protection Agency, Grant No. 2017-17081500003 awarded bythe Intelligence Advanced Research Projects Activity, and Grant No.CBMXCEL-XL1-2-001 awarded by the Defense Threat Reduction Agency throughSubcontract 468746 by Los Alamos National Laboratory (LANL). Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The invention relates generally to microfluidic systems, and moreparticularly to cartridge systems, capacitive pumps, multi-throw valves,and pump-valve systems and applications of the same.

BACKGROUND INFORMATION

The background description provided herein is for the purpose ofgenerally presenting the context of the invention. The subject matterdiscussed in the background of the invention section should not beassumed to be prior art merely as a result of its mention in thebackground of the invention section. Similarly, a problem mentioned inthe background of the invention section or associated with the subjectmatter of the background of the invention section should not be assumedto have been previously recognized in the prior art. The subject matterin the background of the invention section merely represents differentapproaches, which in and of themselves may also be inventions. Work ofthe presently named inventors, to the extent it is described in thebackground of the invention section, as well as aspects of thedescription that may not otherwise qualify as prior art at the time offiling, are neither expressly nor impliedly admitted as prior artagainst the invention.

Microfluidic systems with pumps and control fluidic flows inorgan-on-chip bioreactors and instruments such as perfusion controllers,microclinical analyzers, and microformulators have drawn great attentionof researchers over the past years. Demonstration of these devices hasbeen accomplished using standard soft-lithographic techniques. It isnoted that there are still a multitude of issues, such as problems withalignment of pump and valve fluidics and their actuators, andconnections thereof, stability, portability and adaptability of fluidicsystems, manufacturability and sterilizability, and so on, remainedunresolved.

Therefore, a heretofore unaddressed need exists in the art to addressthe aforementioned deficiencies and inadequacies.

SUMMARY OF THE INVENTION

In one aspect of the invention, the fluidic device comprises a fluidicchip including a body having a first surface and an opposite, secondsurface, one or more channels formed in the body in fluidiccommunications with input ports and output ports for transferring one ormore fluids between the input ports and the output ports, and a fluidicchip registration means formed on the first surface for aligning thefluidic chip with a support structure. The fluidic device also comprisesan actuator configured to engage with the one or more channels at thesecond surface of the body for selectively and individually controllingthe transfer of the one or more fluids through the one or more channelsfrom at least one of the input ports to at least one of the output portsat desired flowrates.

In one embodiment, the fluidic device further comprises a motor tooperably drive the actuator to be activated or deactivated.

In one embodiment, the body of the fluidic chip comprises a first layerand a second layer, each layer having a first surface and an opposite,second surface, wherein the one or more channels are grooved on a firstsurface of the second layer, a second surface of the first layer isplanar and bonded to the first surface of the second layer to seal anopen side of the one or more channels in the first surface of the secondlayer, and the second layer is elastomeric, such that compression of theactuator on a second surface of the second layer causes at least one ofthe one or more channels in the second layer to be occluded, wherein thefirst and second surfaces of the body are coincident with the firstsurface of the first layer and the second surface of the second layer,respectively.

In one embodiment, the fluidic chip registration means is configuredsuch that the fluid chip is allowed for multiple fluid chip orientationswhile maintaining automatic and precise mechanical alignment to thesupport structure.

In one embodiment, the fluidic chip registration means comprises atleast one protrusion protruded from the first surface of the body.

In one embodiment, the least one protrusion is configured to fluidicallycommunicate the one or more channels with interface ports that allowconnection of external tubing to the fluidic chip through a base plate.

In one embodiment, the fluid chip is configured such that one or moreplug-in accessories are addable in or removable from the fluid chip. Inone embodiment, the one or more plug-in accessories comprise capacitors,adjustable fluidic resistors, electrical or electrochemical sensors,photosensors for detecting or tracking bubbles for either bubbledetection or for determining flow rates, flowmeters, manifolds,overpressure relief (blowoff) valves, check valves, bubble traps,injection ports, bioreactors, or a combination of them.

In one embodiment, the fluidic chip is a circular through-plate devicein a radial channel configuration capable of accepting fluidicfunctionality expansion flow-through chips containing adjustable fluidicresistance modules for one or more pumping channels, individual channelpulsation dampening means including fluidic capacitors, pressureequalizing fluidic network for two or more main pumping channelsincluding fluidic shunt capacitors, and/or simultaneous multichannelflow measuring/calibrating module.

In one embodiment, the fluidic device is a rotary planar peristalticmicropump (RPPM).

In one embodiment, the actuator comprises a plurality of rolling membersand a driving member configured such that when the driving memberrotates, the plurality of rolling members rolls along the one or morechannels so as to selectively and individually transfer the one or morefluids through the one or more channels at the desired flowrates.

In one embodiment, the fluidic device is a capacitive pump, wherein theone or more channels comprise one channel having a middle,circumferential portion with two end portions, each end portion beingcoupled to a port through a chamber or a bubble trap, wherein thechamber or bubble trap operably function as capacitor to reduce flow andpressure transients associated with rolling members of the actuatorrolling on or off said channel.

In one embodiment, the chamber has a volume that plays a role inreduction of the flow and pressure transients. In one embodiment, thetwo chambers are identical to or different from one another, and are inany one of geometric shapes.

In one embodiment, the capacitor is a shunt capacitor, or a bubble trapcapacitor.

In one embodiment, the fluidic chip further comprises a ridge formed onthe second surface of the body in relation to said channel for allowingthe actuator to gradually engage and disengage with said channel and aworking fluid to prevent backflow and reducing pulsatility.

In one embodiment, the ridge has ramps with angles for a start and anend of the ramp formed at each end of the ridge for eliminating backflowand stopping flow as the rolling members enter and leave the ridge.

In one embodiment, the fluidic device is a rotary planar valve (RPV)comprising a multi-channel valve, a manifold valve, or a multi-throwvalve.

In one embodiment, each of the one or more channels comprises one ormore sub-channels connected to one or more input ports and one or moreoutputs, wherein all the sub-channels of the one or more channels arespaced-apart in the radial channel configuration.

In one embodiment, the actuator comprises a cage defining a plurality ofspaced-apart openings; a plurality of pop-up members, each pop-up memberretained in a respective opening of the cage and being verticallymovable therein; and a drivehead having a surface and at least onerecess formed on the surface, wherein the cage is placed on the secondsurface of the fluidic chip to constrain each pop-up member in aposition immediately on a respective sub-channel, such that when apop-up member is pressed into the second surface of the fluidic chip, asub-channel that is immediately beneath the pop-up member is compressed,otherwise, said sub-channel is uncompressed; and wherein the driveheadis rotatably engaged with the cage such that as the drivehead rotates ata position, any selected pop-up members positioned in the at least onerecess arise to create open sub-channels corresponding to the selectedpop-up members, thereby selectively unoccluding or occluding fluid flowsthrough desired sub-channels.

In one embodiment, the RPV is a normally closed RPV.

In one embodiment, the at least one recess comprises a plurality oftangential ovoid recesses.

In one embodiment, the plurality of tangential ovoid recesses isconfigured to ensure that there is no “off” position for the pluralityof pop-up members while switching from one input port to another inputport where both input sub-channels connected to said two input ports areclosed at the same time.

In one embodiment, the RPV is a make-before-break valve.

In one embodiment, the fluidic chip and the actuator are configured suchthat there are actuated balls that open and close channels upon whichthey reside, unactuated balls underneath which channels are alwaysclosed, and absent balls underneath which channels are always open,thereby partitioning the valve into a plurality of independentfluid-containing regions separated by the unactuated balls, each regionhaving its own inlet/outlet ports, a group of channels, and actuatedballs such that by a selection of the actuated balls, flows to or fromthe ports within said region are dynamically controllable, whichallowing a plurality of isolated fluidic circuits to exist on a singlechip.

In another aspect of the invention, a cartridge of a fluidic deviceincludes the fluidic device as disclosed above; a support structurehaving segmental openings; a motor plate; standoff plates; and anenclosure hood. As assembled, an assembly of the actuator slides over ashaft of the motor and is fixed in place with a fastening means, themotor is fastened to the motor plate, the standoff plates are fastenedto the enclosure hood through the motor plate, the second surface of thefluidic chip faces the actuator, the fluidic chip registration means onthe first surface of the fluidic chip is received in the segmentalopenings of the support structure, and the support structure is in turnattached securely to the standoff plates

In one embodiment, registration of the fluidic chip registration meansto the segmental openings in fluidic chip support plate preventsrotational and translational movement of the fluidic chip relative tothe cartridge.

In one embodiment, the cartridge further comprises windows for visual orphysical accessing to the actuator and the fluidic chip, wherein thewindows are removably attached to the fluidic support structure and thestandoff plates such that debris ingress is prevented.

In one embodiment, the cartridge further comprises gaskets forpart-to-part sealing so as to prevent moisture and/or air from enteringinto the cartridge.

In one embodiment, the enclosure hood has an electrical feedthrough forallowing electrical communication between the fluidic device andexternal electronics.

In one embodiment, the electrical feedthrough is in the form of a DINconnector or other connector, and is capped to prevent dust or moisturefrom entering into the cartridge.

In one embodiment, the fluidic device further comprises an encoder andcontrol electronics disposed within the enclosure hood.

In one embodiment, the cartridge further comprises a retainer configuredto clamp the fluidic chip to the support structure for maintaining theposition and therefore the alignment of the fluidic chip relative to thesupport structure in case counterforce is applied during handling orintubation of the fluidic chip, wherein such securement also promotesstable compression characteristics between the actuator and the fluidicchip by ensuring contact between the fluidic chip and the supportstructure and planarity of the fluidic chip.

In one embodiment, the cartridge is fluidically connectable to anothercartridge or fluidic device through a fluidic interface connectorcoupled to the fluidic chip registration means registered in the supportstructure.

In yet another aspect of the invention, a pump-valve (P-V) systemincludes a plurality of cartridges disposed on a platform, eachcartridge is disclosed above, wherein the plurality of cartridgescomprises pump cartridges, valve cartridges, or a combination of them;and vials disposed on a platform, for inputting and/outputting one ormore fluids.

In one embodiment, the P-V system further has one or more fluidicinterface connectors coupled to the fluidic chip registration meansregistered in the support structures of cartridges for fluidicallyconnecting one cartridge to another cartridge. In one embodiment, eachof the one or more fluidic interface connectors comprises bioreactorconnector tubes, valve connector tubes, pump tubes, and reservoir tubes,configured to be operably insertable into corresponding ports on each ofbioreactors, valves, pumps, and reservoirs, respectively, fordynamically controlling flows of one or more fluids through the pumpsand the valves into and/or out of the bioreactors.

In one embodiment, the P-V system further has comprising a neurovascularunit (NVU) bioreactor disposed on the platform and coupled to theplurality of cartridges and the vials, and/or a polycarbonate well platedisposed on the platform.

In one embodiment, the plurality of cartridges comprises two pumpcartridges, and the P-V system is a perfusion controller.

In one embodiment, the plurality of cartridges comprises six cartridges,and the P-V system is a 24-channel microformulator system.

In one embodiment, the plurality of cartridges comprises four sets ofcartridges, each set having two valve cartridges and one pump cartridge,and the P-V system is a twenty-four channel transwell microformulatorsystem.

In one embodiment, the plurality of cartridges comprises six valvecartridges and four pump cartridges, and the P-V system ispharmacokinetic sampling module.

These and other aspects of the invention will become apparent from thefollowing description of the preferred embodiment taken in conjunctionwith the following drawings, although variations and modificationstherein may be affected without departing from the spirit and scope ofthe novel concepts of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate one or more embodiments of theinvention and, together with the written description, serve to explainthe principles of the invention. Wherever possible, the same referencenumbers are used throughout the drawings to refer to the same or likeelements of an embodiment.

FIG. 1 shows perspective and exploded views of an existing, open-framerotary planar peristaltic micropump (RPPM) cartridge, which contains themotor, the pump actuator, and the fluidics.

FIG. 2 shows perspective and exploded views of an existing open-framerotary planar valve (RPV) cartridge, which contains the motor, the pumpactuator, and the fluidics.

FIG. 3 shows three fluidics chips for the RPPM and RPV.

FIG. 4 shows how an RPPM and an RPV can be mounted on a caddy thatsupports fluidic vials and an electrochemical sensor to create amicroclinical analyzer, an integrated, autocalibrating microfluidicinstrument that measures the concentration of one or more analytes inmedia that is either drawn into the instrument from an external sourceor from one of the reservoirs. Without the sensor, this device alsofunctions as a single channel microformulator that can deliver upondemand a custom-formulated mixture of analytes that are drawnsequentially from each of the multiple reservoirs.

FIG. 5A shows an exploded view of an enclosed pump cartridge including afluidic chip, actuator, drive motor, encoder, controlling electronics,and housing parts, according to one embodiment of the invention.

FIG. 5B shows an inverted ridge pump fluidic chip, pump actuator, andfluidic chip support plate, according to one embodiment of theinvention.

FIG. 5C shows a retainer assembled to a clamp fluidic chip according toone embodiment of the invention.

FIG. 6A-6B show respectively plan and perspective views of the circular,through-plate implementation of a capacitive pump according to oneembodiment of the invention.

FIG. 6C shows various embodiments of the capacitive pump chip designsand mold components according to the invention.

FIG. 6D demonstrates the effectiveness of a capacitive RPPM to reduceflow pulsatility according to embodiments of the invention.

FIG. 6E demonstrates effects of a hydraulic capacitor on theinstantaneous pump output of a capacitive RPPM according to embodimentsof the invention.

FIG. 6F demonstrates typical output of a single channel of themultichannel pump (channel 5) with or without a capacitor according toembodiments of the invention.

FIG. 6G shows respectively prototyped large shunt capacitor, small shuntcapacitor, and bubble trap capacitor for a capacitive RPPM according toembodiments of the invention.

FIG. 6H shows testing results of flowrates of pumps with a bubble trapcapacitor (top panel), a large and small shunt capacitors (bottompanel), which are compared with that of the pumps without thesecapacitors, according to embodiments of the invention.

FIG. 7 shows an example of a configurable-manifold valve layout, whereingroupings of channels can be mutually isolated by non-actuated balls,allowing a plurality of isolated fluidic circuits to exist on a singlechip.

FIG. 8A shows an exploded view of the enclosed valve cartridge includinga fluidic chip, actuator assembly, drive motor, encoder, controllingelectronics, and housing parts, according to one embodiment of theinvention.

FIG. 8B shows a 25-port valve fluidic chip, valve actuator construct,and fluidic chip support plate, and their alignment and constrainmentcapability, and a valve assembly showing actuator balls in relaxed andcompressed states, with the corresponding channels open and pinchedclosed, respectively, according to one embodiment of the invention.

FIG. 8C shows a cross-sectional view showing an actuator ball within arecess in the actuator, with the corresponding channel open in therelaxed position, according to one embodiment of the invention.

FIG. 8D shows a cross-sectional view showing the actuator and ballcompressing the channel and pinching it closed, according to oneembodiment of the invention.

FIG. 8E is a perspective view of a circular through-plate 25-channelvalve, showing the actuated surface, working channels,registration/alignment protrusions, and interface ports, according toone embodiment of the invention.

FIG. 8F shows a plan view of a 25-port valve with identifying markingsand actuator ball locations, according to one embodiment of theinvention.

FIG. 8G shows a manifold valve according to one embodiment of theinvention.

FIG. 9A illustrates one layout of the two-by-eight open-before-close RPVaccording to one embodiment of the invention.

FIG. 9B shows the concept of a two-by-eight open-before-close RPV withthe A channels open and connected to the output C while the B channelsare closed according to one embodiment of the invention.

FIG. 9C shows the concept of a two-by-eight open-before-close RPV withboth the A and B channels open and connected to the output C accordingto one embodiment of the invention.

FIG. 9D shows the concept of a two-by-eight open-before-close RPV withthe B channels open and connected to the output C while the A channelsare closed according to one embodiment of the invention.

FIG. 9E-9G shows line drawings and FIG. 9H-9J shows photographs thatillustrate the three positions of a two-by-eight open-before-close RPVimplemented using a through-plate circular fluidic chip according to oneembodiment of the invention.

FIG. 9K shows the fluidic chips support plate with segmental openingsand the circular, through-plate fluidic chip for the two-by-eightnormally closed RPV according to one embodiment of the invention.

FIG. 9L shows the valve actuator with eight actuator grooves as requiredfor operation of a normally closed RPV according to one embodiment ofthe invention.

FIGS. 10A-10D show make-before-break vales and their operation statesaccording to embodiments of the invention.

FIG. 11A shows a ribbon fluidic connector that positioned to join a Puckbioreactor, two motor cartridges and four vials containing drugs, media,or waste, according to one embodiment of the invention.

FIG. 11B shows the ribbon fluidic connector with its needle insertedinto the appropriate ports to interconnect a Puck bioreactor, two motorcartridges, and four vials containing drugs, media, or waste, accordingto one embodiment of the invention.

FIG. 11C shows a variety of accessories that can be mounted on acircular through-plate fluidic chip in the closed motor cartridge,according to one embodiment of the invention.

FIG. 11D shows a ribbon fluidic interface connector that could runbetween pump and valve cartridges and the fluidic chip connectionneedles in a μformulator, according to one embodiment of the invention.

FIG. 12A shows how the Puck NVU bioreactor can be merged with thethrough-plate fluidic with an interface fluidic and enclosed motorcartridge to provide a compact means of pumping fluid from inputreservoirs, through the NVU, and then to output reservoirs according toone embodiment of the invention.

FIG. 12B shows slightly different embodiment of FIG. 12A where theinterface fluidic allows the NVU to extend beyond the motor cartridgefor microscopy according to one embodiment of the invention.

FIG. 12C shows a third embodiment where the interface fluidic is in theform of a ribbon fluidic with integral tubing ports such that the motorcartridge is horizontal according to one embodiment of the invention.

FIG. 13A shows how circular through-plate fluidic chip RPPMs and PRVscan be interfaced to the Nortis three-chamber bioreactor according toone embodiment of the invention.

FIG. 13B shows the Nortis chip inserted into the chip receptacleaccording to one embodiment of the invention.

FIG. 13C shows an exploded view of the chip receptacle according to oneembodiment of the invention FIG. 13D shows the assembled chip receptacleaccording to one embodiment of the invention.

FIG. 13E shows how circular through-plate fluidic chip RPPMs and PRVsand ribbon fluidic connectors can simplify the interface to the Nortisthree-chamber bioreactor according to one embodiment of the invention.

FIGS. 14A-14B show a perfusion controller/NVU caddy according to oneembodiment of the invention

FIGS. 14C-14D show μFormulator 24 systems according to one embodiment ofthe invention

FIG. 14E-4F show pharmacokinetic sampling modules—50-port valve,according to one embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described more fully hereinafter withreference to the accompanying drawings, in which exemplary embodimentsof the invention are shown. The invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art. Likereference numerals refer to like elements throughout.

The terms used in this specification generally have their ordinarymeanings in the art, within the context of the invention, and in thespecific context where each term is used. Certain terms that are used todescribe the invention are discussed below, or elsewhere in thespecification, to provide additional guidance to the practitionerregarding the description of the invention. For convenience, certainterms may be highlighted, for example using italics and/or quotationmarks. The use of highlighting and/or capital letters has no influenceon the scope and meaning of a term; the scope and meaning of a term arethe same, in the same context, whether or not it is highlighted and/orin capital letters. It will be appreciated that the same thing can besaid in more than one way. Consequently, alternative language andsynonyms may be used for any one or more of the terms discussed herein,nor is any special significance to be placed upon whether or not a termis elaborated or discussed herein. Synonyms for certain terms areprovided. A recital of one or more synonyms does not exclude the use ofother synonyms. The use of examples anywhere in this specification,including examples of any terms discussed herein, is illustrative onlyand in no way limits the scope and meaning of the invention or of anyexemplified term. Likewise, the invention is not limited to variousembodiments given in this specification.

It will be understood that when an element is referred to as being “on”another element, it can be directly on the other element or interveningelements may be present therebetween. In contrast, when an element isreferred to as being “directly on” another element, there are nointervening elements present. As used herein, the term “and/or” includesany and all combinations of one or more of the associated listed items.

It will be understood that, although the terms first, second, third,etc. may be used herein to describe various elements, components,regions, layers and/or sections, these elements, components, regions,layers and/or sections should not be limited by these terms. These termsare only used to distinguish one element, component, region, layer orsection from another element, component, region, layer or section. Thus,a first element, component, region, layer or section discussed below canbe termed a second element, component, region, layer or section withoutdeparting from the teachings of the invention.

It will be understood that when an element is referred to as being “on,”“attached” to, “connected” to, “coupled” with, “contacting,” etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on,” “directly attached” to, “directly connected”to, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” to another feature may have portions thatoverlap or underlie the adjacent feature.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a,” “an,” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” or “includes” and/or “including” or “has” and/or“having” when used in this specification specify the presence of statedfeatures, regions, integers, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, regions, integers, steps, operations, elements,components, and/or groups thereof.

Furthermore, relative terms, such as “lower” or “bottom” and “upper” or“top,” may be used herein to describe one element's relationship toanother element as illustrated in the figures. It will be understoodthat relative terms are intended to encompass different orientations ofthe device in addition to the orientation shown in the figures. Forexample, if the device in one of the figures is turned over, elementsdescribed as being on the “lower” side of other elements would then beoriented on the “upper” sides of the other elements. The exemplary term“lower” can, therefore, encompass both an orientation of lower andupper, depending on the particular orientation of the figure. Similarly,if the device in one of the figures is turned over, elements describedas “below” or “beneath” other elements would then be oriented “above”the other elements. The exemplary terms “below” or “beneath” can,therefore, encompass both an orientation of above and below.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which the invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the relevant art and thepresent disclosure, and will not be interpreted in an idealized oroverly formal sense unless expressly so defined herein.

As used herein, “around,” “about,” “substantially” or “approximately”shall generally mean within 20 percent, preferably within 10 percent,and more preferably within 5 percent of a given value or range.Numerical quantities given herein are approximate, meaning that theterms “around,” “about,” “substantially” or “approximately” can beinferred if not expressly stated.

As used herein, the terms “comprise” or “comprising,” “include” or“including,” “carry” or “carrying,” “has/have” or “having,” “contain” or“containing,” “involve” or “involving” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to.

As used herein, the phrase “at least one of A, B, and C” should beconstrued to mean a logical (A or B or C), using a non-exclusive logicalOR. As used herein, the term “and/or” includes any and all combinationsof one or more of the associated listed items.

The description below is merely illustrative in nature and is in no wayintended to limit the invention, its application, or uses. The broadteachings of the invention can be implemented in a variety of forms.Therefore, while this invention includes particular examples, the truescope of the invention should not be so limited since othermodifications will become apparent upon a study of the drawings, thespecification, and the following claims. For purposes of clarity, thesame reference numbers will be used in the drawings to identify similarelements. It should be understood that one or more steps within a methodmay be executed in different order (or concurrently) without alteringthe principles of the invention.

One of the objectives of this invention is to refine, extend, and/orintegrate the devices and systems disclosed in our U.S. application Ser.No. 14/651,174, entitled “Normally Closed Microvalve and Applications ofthe Same”, now U.S. Pat. No. 9,618,129; U.S. application Ser. No.14/362,841, entitled “Integrated Human Organ-on-Chip MicrophysiologicalSystems”, now U.S. Pat. No. 9,725,687; U.S. application Ser. No.14/646,300, entitled “Organ on Chip Integration and Applications of theSame”, now U.S. Pat. No. 9,874,285; U.S. application Ser. No.15,191,092, entitled “Interconnections of Multiple Perfused EngineeredTissue Constructs and Microbioreactors, Multi-Microformulators andApplications of the Same”, now U.S. Pat. No. 10,023,832; U.S.application Ser. No. 13/183,287, entitled “Metering Rotary Nanopump,Method of Fabricating Same, and Applications of Same”, now abandoned;U.S. application Ser. No. 15/820,506, entitled “Peristaltic Micropumpand Related Systems and Methods”, now pending; and PCT ApplicationSerial No. PCT/US2019/034285, entitled “Multicompartment MicrofluidicBioreactors, Cylindrical Rotary Valves and Applications of Same”, nowpending. Each of these applications is incorporated herein by referencein its entirety.

In one aspect, this invention includes a rotary planar peristalticmicropump with variable height ridges to avoid the stop-flow and reverseflow associated with existing peristaltic micropumps, pumps withintegrated fluidic capacitors to reduce the oscillations associated withperistaltic pumps, and rotary planar microfluidic valves. The problemswith alignment of pump and valve fluidics and their rotary actuators areeliminated with circular fluidic chips with protrusions thatautomatically align the chip with the fluidic chip support plate of themotor cartridge and enable use of through-plate connections of externaltubing to the network of microfluidic channels that comprise the pumpsand valves within the microfluidic chip.

This invention can be incorporated into an integrated housing thatsimplifies assembly, enables wipe sterilization of all exposed surfaces,and provides electromagnetic and electrostatic shielding of the motor,encoder, and motor control electronics. The pumps can also be equippedwith an integrated, adjustable pressure release valve that limits thepressure delivered by the pump should the output of the pump becomeblocked, for example by debris or a closed valve, or a malfunctioningfluidic connector. When such a pump is used in conjunction with amultiport rotary planar valve, it is then possible for a single pump andvalve to pressurize multiple reservoirs that then can perfuse multipleorgan chips, wells in well plates, or other bio-objects (experimentalchambers). The circular fluidics chip design allows connection to pumpsand valves using removable, ribbon-fluidic connectors and/or additionalfunctional modules such as flow capacitors or resistors. The concept offluidic ribbon connectors can be extended to create peristaltic pumpsthat can simultaneously pump multiple lines of fluid in the forward orreverse directions.

Finally, the precise fluidic control afforded by these pumps and valvesand the computerized microcontroller that operates them can be used in aclosed-loop manner with an imaging or other optical time-of-flightdetector to track the speed by which a bubble that is intentionallyintroduced into the fluidic moves along a selected length of tubing orchannel so as to calibrate flowrate of the pump and valve combination.One embodiment of this method utilizes a pair of optical bubbledetectors to detect a gas bubble that is purposely introduced throughone of the valve positions. In this method, a single bubble isintroduced and pumped to the location of the first of a pair of anoptically coupled light-emitting diode (LED) and a photodetector, termedthe bubble detector that can determine the arrival time at the firstdetector. The difference in the index of refraction of the bubble andthe water within the tube affects the focusing of the light from the LEDso that the photodetector can readily identify the arrival or departureof the leading or trailing edge of the bubble. Once detected by thefirst bubble detector, the bubble is then allowed to progress to thesecond bubble detector, so as to allow determination of the timeinterval between the appearance of the leading or trailing edge of thebubble, or both, at each of the two bubble detectors. Given that thedistance between the detectors is known and fixed, the time differenceenables immediate, real-time calibration of the flow velocity. Thebubble can be pumped back and forth at multiple pump rates and withvarious valve combinations in order to characterize the systems pumpingperformance and provide calibration data. The bubble-tracking flow meterwith its two detectors can simply clip onto the outside of a length oftubing connected to the pump, or can be incorporated into an accessorythat plugs directly into the pump. In contrast, a typicalthermal-dilution time of flight flow meter costs much more than twophotodiodes and two LEDs, and the tubing must be interrupted andattached to the thermal-dilution flow meter. In addition, the nature ofthe fluid being pumped affects the calibration of the sensor. Theautomated pump and valve control offered by this invention allowsautomated insertion of the bubble through an appropriate valve port,measurement of the velocity of each bubble as a function of pump speedfor each of the desired pump speeds and valve settings, and thenautomated ejection of the bubble by reverse flow through the valve bywhich the bubble was introduced. In another embodiment, a sensor array(or camera) incorporated into the accessory flow meter is used todetermine time of flight of the bubble.

All of these modular devices can be combined into multi-functionalmicrofluidic systems such as perfusion controllers, microclinicalanalyzers, microformulators and other fluidic control and analysissystems.

In our previous patents and patent applications, we described a modularapproach to control and sensing of organs-on-chips using rotary planarperistaltic micropumps (RPPMs) and rotary planar valves (RPVs). Thesepumps and valves are implemented in a fluidic cartridge that containsthe mechanical, electrical, and microfluidic components necessary foroperation of the pumps or valve. The advantage of this approach is thatmore complex systems can be quickly configured from different modulescreated by one or more cartridge. Furthermore, changes to a particularcartridge component can be implemented quickly and easily propagated tomultiple different systems. We now describe the design and fabricationof cartridges that we have used prior to the present invention.

FIG. 1 shows a pump cartridge 100 as described in our previous patentsand patent applications. Pump fluidic chip 101 is made of a siliconeelastomer or other elastomeric material and bonded to or placed on aglass slide 102 that is contained within alignment frame 103 which isattached with screws 104 to fluidic chip support plate 105 made ofpolycarbonate or other material. Fluidic chip support plate 105 isattached to standoffs 106 with machine screws 107. Nubbins 108 that matewith keyhole recesses (not shown) may be secured to fluidic chip supportplate 105 to allow assembly 100 to be affixed to a substructure (notshown) that supports the cartridge.

Motor 109 is fastened to lower motor plate 110 with machine screws 111.Upper motor plate 112 is supported by upper-tier standoffs 113 andattached to lower-tier standoffs 106 with machine screws 114, therebysecuring lower motor plate 110.

At the center of pump actuator 115 is brass hub 116, which slides overmotor shaft 117 and is fixed in place with set screw 118. Rollerbearings 119 are affixed to hub 116 with shoulder screws 120, and rollon the surface of pump chip 101 when actuator 115 is rotated bydouble-shafted motor 209.

There are a number of limitations to this design, most notably that themotor, with its complex external surfaces, is difficult to sterilize foroperation inside of a sterile cell- or tissue-culture incubator. Theplates require a large number of holes for access and attachment, andthis in turn increases the cost of the cartridge. There are a largenumber of exposed components, such as screws, plates, standoffs, andframes whose manufacturing tolerances are critical to the properoperation of the cartridge. The many surfaces and interfaces in thecartridge, particularly in the laminations of the motor, can readilytrap bacteria and fungal spores in a manner that is difficult orimpossible to decontaminate or sterilize.

Similar issues arise with the valve cartridges. FIG. 2 illustrates thatconsistent with the pump in FIG. 1, the same design approach can be usedto create the rotary planar valve (RPV) cartridge 200.

Valve fluidic chip 201 is made of a silicone elastomer or otherelastomeric material and is positioned between fluidic chip supportplate 105 and ball cage 202, which constrains movement of balls 203 tothe vertical axis via holes 204 within which the balls reside. Ball cage202 slides over lower-tier standoffs 106, thereby preventing rotationalmovement of ball cage 202 and balls 203. Fluidic chip support plate 105is attached to standoffs 106 with machine screws 107. Nubbins 108 thatmate with keyhole recesses (not shown) may be secured to fluidic chipsupport plate 105 to allow assembly 200 to be affixed to a substructure(not shown).

The double-shafted motor 209 is fastened to motor plate 110 with machinescrews 111. Encoder plate 212 is supported by upper-tier standoffs 113and attached to lower-tier standoffs 106 with machine screws 114,thereby securing lower motor plate 110.

Valve actuator 215 slides over lower motor shaft 217 and is fixed inplace with set screw 218. Topography on the lower face of valve actuator215 causes balls 203 to travel along the vertical axis as actuator 215is rotated by motor 209. Balls that are forced down into the surface offluidic chip 201 compress channels positioned under them, therebypinching off and closing those channels to fluid movement.

Encoder 219 is mounted to upper motor shaft 220 of the double-shaftedmotor 209 for motor position feedback to the controller (not shown).

There are manufacturing and sterilization issues with this design aswell. The encoder is vulnerable to microbial contamination that couldreadily migrate into the interior of the device. The encoder electronicsare not protected from either static discharge or electromagneticinterference. The alignment of the fluidic chip on the fluidic chipsupport plate is difficult to adjust with respect to the ball cage andactuator, since the valve fluidic is auto-adhered to the fluidic supportplate and cannot be moved laterally without removing the fluidicssupport plate from the cartridge.

The limitations of the pump and valve cartridges are magnified by thelimitations in the design, manufacture, and operation of the fluidicchips, as shown in FIG. 3. Fluidic chips 101, 201, 301 are made of asilicone rubber material or other elastomeric material. Chips 101, 201,301 are comprised of two layers of elastomeric material, for example,fluidic layer 302, and membrane layer 303, bonded together with plasmaor corona activation or another procedure. Voids creating channels orother features may be located in the upper layer, lower layer, or bothlayers.

Access ports 304 are punched or cast into the material and interfacewith channels 305 or other features within the chips. Tubing (not shown)of larger diameter than that of ports 304 is pressed into the ports,creating a seal and allowing for connections between the fluidic chipand external implements (not shown). Port protrusions 306 may beincluded on either layer to enhance mechanical stability and sealingefficacy in the port regions and/or for alignment/registration purposes.

The need to locate tubing ports only on the periphery of the fluidicchip required that the fluidic chip extend far from the active areadefined by the RPPM and RPV actuators, which increases the overalldimensions of the pump and valve fluidic chips and limits the number ofdevices that can be produced on a single soft-lithographic mold. For thepumps, the insertion of tubes into the microfluidic ports must be doneby reaching into the device, between the motor and fluidic supportplates, and the device can only be attached to a supporting substructurein limited ways. For the pump cartridge, the tubing ports for the pumpfluidic chip are free-standing, making it difficult to attach tubingwithout flexing the fluidic or disturbing adjacent tubes.

The appeal of the modular, cartridge approach is that it simplifiesperfusion control and in-line analysis of organs-on-chips and multiplewells in a well plate over what was previously possible, and it allowsstandardized modules to be configured, and reconfigured, as required tocreate complex fluidic control and sensing instruments.

FIG. 4 shows an exemplary application of pumps 100 and valves 200 as aMicroClinical Analyzer 400. Pump 100 and valve 200 are secured withnubbins 108 to keyhole slots (not pictured) in substructure 401. Liquidmay be selected by the valve 200, withdrawn from reservoir vial 402 bypump 100, and sent through tubing (not pictured) and into an analyticchamber (not pictured) within housing 403 that contains electrode 404 orother device. In some applications, the pump/valve combination may beused to direct waste into a waste container. Magnets 405 pressed intoholes in motor plate 112 and encoder plate 212 allow for mounting ofauxiliary equipment such as disconnects, manifolds, additional reservoirvials, temperature-controlling apparatus, etc. (not shown).

It is noted that the microclinical analyzer can be used as asingle-channel microformulator that can mix on demand five differentreagents into a single fluid stream with automated temporal control ofthe concentration of each reagent. The two-cartridge unit shown can becombined with a twenty-five channel valve to custom-formulate media toeach well in a well plate, with an extra channel for flushing the valve,and an identical unit can be used to withdraw fluid from each of thosewells and direct it to a particular location for analysis. Eight ofthese three motor units can then be combined to create a multiwellmicroformulator that can address each well in a 96-well plate, asdescribed by us in great detail in previous patent applications.

The resulting multi-cartridge instruments that are created using theexisting open-frame cartridge design are subject to the limitations ofthe cartridges discussed above, particularly sterilization. Furthermore,these instruments have a large number of tubes that connect theindividual components of each cartridge and there is no straightforwardway to connect these cartridges by means of mass-produced multi-channelfluidic interconnects. We have previously introduced the concept ofribbon fluidic interconnects in the multiwell microformulator, but themeans by which these ribbons are connected to individual RPPM and RPVcartridges remained unresolved.

As demonstrated in this disclosure, the approaches discussed above maynot be as effective as those disclosed in this invention that discloses,among other things, a fluidic device: a rotary planar micropumps (RPPMs)or a rotary planar valves (RPVs), and cartridge systems in which thefluidic chips that form the RPPMs or the RPVs are constructed andmounted in their motor cartridges and connected to other fluidic objectssuch as other pumps, valves, reservoirs, bioreactors, or analyticalinstruments.

In one aspect of the invention, the fluidic device comprises a fluidicchip that includes a body having a first surface and an opposite, secondsurface, one or more channels formed in the body in fluidiccommunications with input ports and output ports for transferring one ormore fluids between the input ports and the output ports, and a fluidicchip registration means formed on the first surface for aligning thefluidic chip with a support structure. The fluidic device furthercomprises an actuator configured to engage with the one or more channelsat the second surface of the body for selectively and individuallytransferring the one or more fluids through the one or more channelsfrom at least one of the input ports to at least one of the output portsat desired flowrates.

In one embodiment, the fluidic device further comprises a motor tooperably drive the actuator to be activated or deactivated.

In one embodiment, the fluidic device further comprises a computer ormicrocontroller to control the operation of the pumps and valves andallow their synchronous operation as a microformulator, a microclinicalanalyzer, or with a variety of accessories, including bubble-trackingflow meters.

In one embodiment, the body of the fluidic chip comprises a first layerand a second layer, each layer having a first surface and an opposite,second surface, wherein the one or more channels are grooved on a firstsurface of the second layer, a second surface of the first layer isplanar and bonded to the first surface of the second layer to seal anopen side of the one or more channels in the first surface of the secondlayer, and the second layer is elastomeric, such that compression of theactuator on a second surface of the second layer causes at least one ofthe one or more channels in the second layer to be occluded, wherein thefirst and second surfaces of the body are coincident with the firstsurface of the first layer and the second surface of the second layer,respectively.

In one embodiment, the fluidic chip registration means is configuredsuch that the fluid chip is allowed for multiple fluid chip orientationswhile maintaining automatic and precise mechanical alignment to thesupport structure.

In one embodiment, the fluidic chip registration means comprises atleast one protrusion protruded the first surface of the body.

In one embodiment, the least one protrusion is configured to fluidicallycommunicate the one or more channels with interface ports that allowconnection of external tubing to the fluidic chip through a base plate.

In one embodiment, the fluid chip is configured such that one or moreplug-in accessories are addable in or removable from the fluid chip. Inone embodiment, the one or more plug-in accessories comprise capacitors,adjustable fluidic resistors, electrical or electrochemical sensors,photosensors for detecting or tracking bubbles for either bubbledetection or for determining flow rates, flowmeters, manifolds,overpressure relief (blow-off) valves, check valves, bubble traps,injection ports, bioreactors, or a combination of them.

In one embodiment, the fluidic chip is a circular through-plate in aradial channel configuration capable of accepting fluidic functionalityexpansion flow-through chips containing adjustable fluidic resistancemodules for one or more pumping channels, individual channel pulsationdampening means including fluidic capacitors, pressure equalizingfluidic network for two or more main pumping channels including fluidicshunt capacitors, and/or simultaneous multichannel flowmeasuring/calibrating module.

In one embodiment, the fluidic device is an RPPM.

In one embodiment, the actuator comprises a plurality of rolling membersand a driving member configured such that when the driving memberrotates, the plurality of rolling members rolls along the one or morechannels so as to selectively and individually transferring the one ormore fluids through the one or more channels at the desired flowrates.

In one embodiment, the fluidic device is a capacitive pump, wherein theone or more channels comprise one channel having a middle,circumferential portion with two end portions, each end portion beingcoupled to a port through a chamber or a bubble trap, wherein thechamber or bubble trap operably function as capacitor to reduce flow andpressure transients associated with rolling members of the actuatorrolling on or off said channel.

In one embodiment, the chamber has a volume that plays a role inreduction of the flow and pressure transients. In one embodiment, thetwo chambers are identical to or different from one another, and are inany one of geometric shapes.

In one embodiment, the capacitor is a shunt capacitor, or a bubble trapcapacitor.

In one embodiment, the capacitors are series capacitors, in line withthe input or output channel of the pump, or both.

In one embodiment, the capacitors are both series and shunt capacitorsto provide a particular frequency-damping characteristic.

In one embodiment, the fluidic chip further comprises a ridge formed onthe second surface of the body in relation to said channel for allowingthe actuator to gradually engage and disengage with said channel and aworking fluid to prevent backflow and reducing pulsatility.

In one embodiment, the ridge has ramps with angles for a start and anend of the ramp formed at each end of the ridge for eliminating backflowand stopping flow as the rolling members enter and leave the ridge.

In one embodiment, the fluidic device is an RPV comprising amulti-channel valve, a manifold valve, or a multi-throw valve.

In one embodiment, each of the one or more channels comprises one ormore sub-channels connected to one or more input ports and one or moreoutputs, wherein all the sub-channels of the one or more channels arespaced-apart in the radial channel configuration.

In one embodiment, the actuator comprises a cage defining a plurality ofspaced-apart openings; a plurality of pop-up members, each pop-up memberretained in a respective opening of the cage and being verticallymovable therein; and a drivehead having a surface and at least onerecess formed on the surface, wherein the cage is placed on the secondsurface of the fluidic chip to constrain each pop-up member in aposition immediately on a respective sub-channel, such that when apop-up member is pressed into the second surface of the fluidic chip, asub-channel that is immediately beneath the pop-up member is compressed,otherwise, said sub-channel is uncompressed; and wherein the driveheadis rotatably engaged with the cage such that as the drivehead rotates ata position, any selected pop-up members positioned in the at least onerecess arise to create open sub-channels corresponding to the selectedpop-up members, thereby selectively unoccluding or occluding fluid flowsthrough desired sub-channels.

In one embodiment, the RPV is a normally closed RPV.

In one embodiment, the at least one recess comprises a plurality oftangential ovoid recesses.

In one embodiment, the plurality of tangential ovoid recesses isconfigured to ensure that there is no “off” position for the pluralityof pop-up members while switching from one input port to another inputport where both input sub-channels connected to said two input ports areclosed at the same time.

In one embodiment, the RPV is a make-before-break valve.

In one embodiment, the fluidic chip and the actuator are configured suchthat there are actuated balls that open and close channels upon whichthey reside, unactuated balls underneath which channels are alwaysclosed, and absent balls underneath which channels are always open,thereby partitioning the valve into a plurality of independentfluid-containing regions separated by the unactuated balls, each regionhaving its own inlet/outlet ports, a group of channels, and actuatedballs such that by a selection of the actuated balls, flows to or fromthe ports within said region are dynamically controllable, whichallowing a plurality of isolated fluidic circuits to exist on a singlechip.

In another aspect of the invention, a cartridge of a fluidic deviceincudes the fluidic device as disclosed above; a support structurehaving segmental openings; a motor plate; standoff plates; and anenclosure hood. As assembled, an assembly of the actuator slides over ashaft of the motor and is fixed in place with a fastening means, themotor is fastened to the motor plate, the standoff plates are fastenedto the enclosure hood through the motor plate, the second surface of thefluidic chip faces the actuator, the fluidic chip registration means onthe first surface of the fluidic chip is received in the segmentalopenings of the support structure, and the support structure is in turnattached securely to the standoff plates

In one embodiment, registration of the fluidic chip registration meansto the segmental openings in fluidic chip support plate preventsrotational and translational movement of the fluidic chip relative tothe cartridge.

In one embodiment, the cartridge further comprises windows for visual orphysical accessing to the actuator and the fluidic chip, wherein thewindows are removably attached to the fluidic support structure and thestandoff plates such that debris ingress is prevented.

In one embodiment, the cartridge further comprises gaskets forpart-to-part sealing so as to prevent moisture and/or air from enteringinto the cartridge.

In one embodiment, the enclosure hood has an electrical feedthrough forallowing electrical communication between the fluidic device andexternal electronics.

In one embodiment, the electrical feedthrough is in the form of a DINconnector or other connector, and is capped to prevent dust or moisturefrom entering into the cartridge.

In one embodiment, the fluidic device further comprises an encoder andcontrol electronics disposed within the enclosure hood.

In one embodiment, the cartridge further comprises a retainer configuredto clamp the fluidic chip to the support structure for maintaining theposition and therefore the alignment of the fluidic chip relative to thesupport structure in case counterforce is applied during handling orintubation of the fluidic chip, wherein such securement also promotesstable compression characteristics between the actuator and the fluidicchip by ensuring contact between the fluidic chip and the supportstructure and planarity of the fluidic chip.

In one embodiment, the cartridge is fluidically connectable to anothercartridge or fluidic device through a fluidic interface connectorcoupled to the fluidic chip registration means registered in the supportstructure.

In yet another aspect of the invention, a pump-valve (P-V) systemincludes a plurality of cartridges disposed on a platform, eachcartridge is disclosed above, wherein the plurality of cartridgescomprises pump cartridges, valve cartridges, or a combination of them;and vials disposed on a platform, for inputting and/outputting one ormore fluids.

In one embodiment, the P-V system further has one or more fluidicinterface connectors coupled to the fluidic chip registration meansregistered in the support structures of cartridges for fluidicallyconnecting one cartridge to another cartridge. In one embodiment, eachof the one or more fluidic interface connectors comprises bioreactorconnector tubes, valve connector tubes, pump tubes, and reservoir tubes,configured to be operably insertable into corresponding ports on each ofbioreactors, valves, pumps, and reservoirs, respectively, fordynamically controlling flows of one or more fluids through the pumpsand the valves into and/or out of the bioreactors.

In one embodiment, the P-V system further has comprising a neurovascularunit (NVU) bioreactor disposed on the platform and coupled to theplurality of cartridges and the vials, and/or a polycarbonate well platedisposed on the platform.

In one embodiment, the plurality of cartridges comprises two pumpcartridges, and the P-V system is a perfusion controller.

In one embodiment, the plurality of cartridges comprises six cartridges,and the P-V system is a 24 channel microformulator system.

In one embodiment, the plurality of cartridges comprises four sets ofcartridges, each set having two valve cartridges and one pump cartridge,and the P-V system is a twenty-four channel transwell microformulator 24transwell system.

In one embodiment, the plurality of cartridges comprises six valvecartridges and four pump cartridges, and the P-V system ispharmacokinetic sampling module.

According to the invention, the fluidic chip registration format allowsfor multiple chip orientations while maintaining automatic and precisemechanical alignment. The valve fluidic chip with integrated protrusionsallow for automatic and precise alignment to the supporting structure,and therefore the pump actuator. The fluidic chip format with a radialchannel configuration capability allows actuation of multiple channels,individually or in groups, while preventing undesired actuatorinterference with other channels.

Furthermore, according to the invention, the valve having multipleports, any of which may be used or not used, provides enhancedversatility and adaptability. A multi-port valve fluidic chip havingcircular footprint allows configurations that equalize path length andmagnitude of fluid resistance across any incorporated channels. Astandard format for fluidic chips that allows interchangeability betweenpumping capability and switching capability in the same or similarinstrument. the valve chip that can serve as a manifold (single ormultiple inputs, single to multiple outlets) by omitting actuator ballsand attached downstream from individual pumps.

Moreover, according to the invention, the fluidic chip format allowsplug-in accessories to be added or removed. Accessories may includecapacitors, adjustable fluidic resistors, electrical or electrochemicalsensors, photosensors for detecting or tracking bubbles for eitherbubble detection or for determining flow rates, flowmeters, manifolds,overpressure relief (blow-off) valves, check valves, bubble traps,injection ports, bioreactors, etc. Accessories may bedaisy-chained/stacked.

These and other aspects of the present invention are further describedbelow. Without intent to limit the scope of the invention, examples andtheir related results according to the embodiments of the presentinvention are given below. Note that titles or subtitles may be used inthe examples for convenience of a reader, which in no way should limitthe scope of the invention. Moreover, certain theories are proposed anddisclosed herein; however, in no way they, whether they are right orwrong, should limit the scope of the invention so long as the inventionis practiced according to the invention without regard for anyparticular theory or scheme of action.

Fluidic Device Cartridges

Many biological experiments that may use the devices described hereinrequire environments that are not as friendly to mechatronic devices asthey are to biology. These environmental hazards include high humidity,the possibility of fungal, bacterial, or other microbial contamination,splashes and sprays of cleaners, sterilants, and conductive, salt-richmedias, plus the potential for unwanted grounding/electricalnoise/static discharge. These concerns are able to be overcome byincreasing the separation between the environment and the device. Thedevice described herein (including the installed pump, valve, or otherfluidic chip as shown) protects the sensitive electronics and actuationhardware from the various liquids etc. that are used in theseexperiments while also allowing for other chemicals to be used to easilyspray or wipe the outside of the device in order to decontaminate itprior to use in an experiment. This enclosure also allows for internalparts to be replaced and upgraded without major modification to theoutside of the device, preventing the later addition of locations thatmay harbor pockets of contamination. To further this goal, all externalsurfaces, including seams between mating parts, are as smooth as ispractical.

The devices described herein are designed with adaptability in mind.This allows the experimenter using the apparatus to dictate whatconfiguration the device should be in to run the experiments. This isrealized through the simple processes of replacing the fluidic, being ofstandard external design, to that of another type such as a pump orvalve, the relocation of mounting nubbins to facilitate diversity ofmounting orientations, and/or swapping existing end windows/standoffplates to versions designed to assist in making fluidic connections,typically achieved by adding holes. This configuration supports directlytubing from the experiment to the elastomeric fluidic, indirectly totraditional Upchurch/IDEX bulkhead connectors attached to the windows orstandoff plates and plumbed to the fluidic, or some otherconnector-based interface that can be attached via the windows. Theenclosure hood is also sized such that additional sensor and electricalcontrol options can easily be fit within it, further decreasingcomplexity of use and setup by the experimenter. Finally, there arethree accessory mount locations: using either of the window mount screwlocations (regardless if windows are installed), or the pair of holes onthe bottom over which the nubbins may be mounted. All three locationsutilize the same hole size, spacing, and thread, as to allow accessoriesto be added interchangeably between locations.

In one exemplary embodiment, FIG. 5A shows an assembly of an enclosedpump cartridge with an enclosure that supports the features of thisinvention, which allows for full enclosure of fluidic chip 501 withinthe assembly 500 and access to external plumbing (not shown). Outersurfaces of the assembly may be sterilized without affecting sensitiveinner-workings of the instrument.

Fluidic chip support plate 505 is attached to standoff plates 506 withmachine screws 507. Optional, removable windows 508 allow for access toactuator 516 and fluidic chip 501. Windows 508 mate with adjacentfluidic support plate 505, standoff plates 506, and fluidic supportplate 505 such that most debris ingress is prevented. This and otherpart-to-part seals can be made to be water-tight and/or air-tight withthe addition of a gasket (not shown).

Motor 209 is fastened to motor plate 510 with machine screws 511.Standoff plates 506 are fastened to enclosure hood 512 through motorplate 510 with machine screws 513. Electrical feedthrough 514 allowselectrical communication between the device and external electronics andmay take the form of a DIN connector or other connector, and may becapped to prevent dust or moisture from entering assembly 500. Onboardmotor 209, encoder 219, and control electronics 515 may be includedwithin hood 512. Nubbins 108 that mates with keyhole recesses may besecured in a number of locations on assembly 500 to allow it to bemounted to a substructure (not shown). Threaded holes for attachingnubbins 108 or windows 508 may also be used to mount other accessories(not shown).

In a manner similar to the pump actuator assembly shown in FIG. 1, pumpactuator assembly 516 slides over motor shaft 217 and is fixed in placewith a set screw. The roller bearings are affixed to the hub withshoulder screws, and roll on the actuated surface of pump chip 501 whenactuator assembly 516 is rotated by motor 209.

FIG. 5B shows the geometric relation between pump actuator assembly 516,circular through-plate fluidic 501, and fluidics support plate 505, andshows how the protrusions 506 mate with segmental openings 520 in thefluidic support plate 505.

Registration of protrusions 506 to segmental openings 520 in fluidicchip support plate 505 prevents rotational and translational movement offluidic chip 501 relative to the assembly 500.

The present embodiment shows the fluidic chip 501 with protrusions 506as being circular. Other embodiments could utilize square, rectangular,or other shape fluidic chips as dictated by the application and thepracticalities of chip production.

In another embodiment shown in FIG. 5C, retainer 517 is used to clampfluidic chip 501 to fluidic chip support plate 518. Retainer 517 isattached to baseplate 518 with machine screws 519. Retainer 517maintains position and therefore alignment of fluidic chip 501 relativeto fluidic chip support plate 518 in case counterforce is applied duringhandling or intubation of fluidic chip 501. Such securement alsopromotes stable compression characteristics between actuator 516 andfluidic chip 501 by ensuring contact between fluidic chip 501 andfluidic chip support plate 505. Furthermore, addition of retainer 517allows chip 501 and fluidic support plate 518 to be removed/transferredwithout risking disruption of chip-baseplate alignment.

While the fluidics could be produced by automated, commercial injectionmolding, the novel and appealing of embodiments of this design accordingto the invention is that fabrication techniques we developed to createthe circular, through-plate fluidic chips are more repeatable, do notrequire solvents or a hood, and can be used to fabricate larger devicesthat is the case with conventional photolithographic methods to producemicrofluidic masters.

According to the invention, the retainer counters any forces generatedby the intubation of fluidic chip, thereby securing it in place relativeto the housing assembly/actuator. The retainer will increase theplanarity of the fluidic chip, and may add additional resistance againsttorque applied by the actuator to the fluidic chip. According to theinvention, the retainer can promote stable compression characteristicsand stable chip-baseplate alignment; allow chip and baseplate to beremoved/transferred without risking disruption of chip-baseplatealignment; and minimize undesirable wear of fluidic chip.

Capacitive Pumps

It is noted that rotary planar peristaltic micropumps may produce highamplitude pulses which are caused by the roll-on and roll-off of therollers over the channels, and the stepping of the stepper motor. Inaddition, when run in a multi-chambered device separated by a thinmembrane, these pulses can cause differential flow across the membrane.Differential flow across a membrane in an organ chip can be potentiallycell lethal.

In one aspect of the invention, a capacitive pump is provided to solvethese problem. The capacitive pump can reduce flow and pressuretransients associated with the rollers rolling on or off the channel. Incertain embodiments, resistor/capacitor pairs are added to the pumps.Increased length of on-chip supply/waste channels adds to overallresistance of the pump circuit, and cavities capped with diaphragms addcapacitance to absorb/smooth pulsatility peaks.

FIG. 6A-6B show respectively plan and perspective views of the circular,through-plate implementation of a capacitive pump according to oneembodiment of the invention. In this example, the through-plate fluidicpump chip 601 includes a fluidic channel 630 having a middle,circumferential portion with two end portions 632 and 634, which arerespectively extended to chambers (or bladders or cavities) 635 and 636,or bubble traps, which in turns, are extended to a first port 631 and asecond port 633, respectively. The chambers 635 and 636 can be same ordifferent, and can be any one of geometric shapes. Operably, thechambers 635 and 636 function as capacitors to reduce flow and pressuretransients associated with the rollers rolling on or off the channel630. In one embodiment, the through-plate fluidic pump chip 601 alsoincludes a fluidic chip registration means including surroundingstandoff plates/tabs/flanges/protrusions 606, which allows for automaticand precise mechanical alignment to the supporting structure, also formultiple chip orientations while maintaining automatic and precisemechanical alignment. In one embodiment, the through-plate fluidic pumpchip 601 may have a ridge 638 formed in relation to the channel 630,with angles for the start and end of the ramp at each end of the ridgechosen so as to eliminate backflow and stopped flow as the pump rollersenter and leave the ridge, which allows the actuator to gradually engageand disengage with the channel 630 and working fluid, thereby preventingbackflow and reducing pulsatility.

As shown in FIGS. 6G-6H below, the size/volume of the chamber of thecapacitor, or the bubble trap, is a very important means to reduce theamplitude of the flow pulses.

FIG. 6C shows various embodiments of the capacitive pump chip designsand details of their molds according to the invention.

FIG. 6D demonstrates the effectiveness of a capacitive RPPM to reduceflow pulsatility according to embodiments of the invention.

FIG. 6E demonstrates effects of a hydraulic capacitor on instantaneouspump output of a capacitive RPPM according to embodiments of theinvention.

FIG. 6F demonstrates the typical output of a single channel of themultichannel pump (channel 5) with or without a capacitor according toembodiments of the invention.

In order to characterize the role of the size/volume of the chamber insmoothing out the flow spikes, two shunt capacitor types are designedand fabricated for a micropump according to embodiments of theinvention. The two types fabricated are a small and large capacitor. Asshown in FIG. 6G, in one embodiment, large capacitor (top) has channelwidth, W=0.5 mm, chamber diameter, D=10 mm, port-to-port length, L=19mm; and in another embodiment, the small capacitor (middle) has channelwidth, W=0.5 mm, chamber diameter, D=6 mm, and port-to-port length, L=19mm.

In addition, FIG. 6G also shows a bubble trap functioning as a capacitorfor a micropump according to yet another embodiment of the invention.The bubble trap is disclosed in our U.S. patent application Ser. No.16/049,025, which is incorporated herein by reference in its entirety,which is originally designed to prevent bubbles from entering an organchip. A large forest of posts with a thin 100 μm membrane separating thebubble capture area from the bubble release chamber to allow diffusionof air through the membrane either passively or actively with vacuum.The port-to-port length, L=17 mm.

FIG. 6H shows testing results of flowrates of pumps with a bubble trapcapacitor (top panel), a large and small shunt capacitors (bottompanel), which are compared with that of the pumps without thesecapacitors.

For the shunt capacitors, the large and small shunt capacitors areimpossible to load without capturing some air bubbles inside thecapacitor bladder/chamber. Most of the captured air can be flushed outbut not all of the air which can allow a trapped bubble to continue togrow and be released downstream into an organ chip mid experimentresulting in cell death and experiment failure.

For the bubble trap capacitors, the advantage of the bubble trap is thatif air bubbles are trapped, they are released passively via diffusionthrough the 100 μm membrane, and if desired actively with a vacuumapplied via the vacuum port. The data suggests that the bubble trap andthe large format shunt capacitor both work, but it is difficult to loadthe large capacitor without capturing bubbles. The bubble trap requiresthe fabrication of more layers than the shunt capacitor as it is a fivelayered device whereas the shunt capacitor is a three layered device.

Hence when running the ridge pumps with organ chips users can opt topurchase bubble traps for preventing bubble introduction into theirdevices and/or for capacitors to smooth out the flow profile. This isespecially beneficial in a device like the NVU Organ Chip where smoothflow on both sides of the membrane is crucial to prevent membranecross-talk.

Multi-Port Valves

FIG. 7 shows schematically another configuration of the 25-port valvefluidic described above. By utilizing a combination of actuated balls(that open and close the channel upon which they reside) such as 710,unactuated balls (the channel is always closed) such as 720, and absentballs (channel is always open) such as 730 and 731, a valve chip can beconfigured in many ways. FIG. 7 shows one such exemplary configurationwherein the device is split into four independent fluid-containingregions 701, 702, 703, and 704, each with its own inlet/outlet ports,common channel, and in this case a selection of actuated balls. Theunactuated balls, denoted by filled circles, separate these regionswhile actuated balls shown by empty circles allow for dynamic flowcontrol to or from the port in question. Any port or region can bedesigned such that a ball separates it from its neighbors. Each regionacts as a manifold, allowing for the controlled splitting or combiningof various fluids potentially including multiple inlets and multipleoutlets spread over multiple port-containing protrusions. Depending onthe actuator utilized with a given ball configuration, the appropriateballs may be actuated independently as in the typical 25-portembodiment, in pairs or groups as in a make-before-break design, and/orin sets such that each independent region is actuated the same, e.g.,the first port of each region is open at the same time.

As with the enclosed pump cartridge, as shown in FIGS. 5A-5C, ease ofcleaning, upgrading, and protecting the electronics are furthered byadding a matching enclosure around the valves. These valves allow forthe direction of flow to or from a microfluidic channel/device and canbe manufactured from elastomer in many different configurations andnumber of ports. These devices allow for the autonomous control softwareto flow specific chemicals and medias to various specific devices and,though use of multiplexing, approximate various concentration curves.This allows for the automation of various types of biologicalexperiments, increasing repeatability and throughput. A selection ofsample valve and pump fluidic designs are included in this document.These together allow for a novel level of experiment control andautomation.

Referring to FIG. 8A, an enclosed valve cartridge 800 is shown accordingto one embodiment of the invention. This configuration utilizes theposition data provided by motor encoder 219 as noted in FIG. 5A to alignvalve actuator 816 in order to open specific channels in the valvefluidic 801.

Valve actuator 816 is a cylinder made from acetal resin or othermaterial. Topography on the lower face of valve actuator 816, such asgroove 817, pockets, or similar features, displaces balls 818 asactuator 816 is rotated. Ball cage 819 constrains movements of balls 818to the vertical axis via holes 820 within which the balls reside. Ballcage 819 is constrained against interior edges of surrounding standoffplates/tabs/flanges 506, thereby preventing rotational movement of ballcage 819 and balls 818. The surrounding standoff plates/tabs/flanges 506allows for multiple chip orientations while maintaining automatic andprecise mechanical alignment.

Balls 818 that are forced down into the surface of fluidic chip 801compress channels (not pictured here) positioned under them, therebypinching off and closing those channels to fluid movement.

FIG. 8B shows an exploded view of a 25-channel (port) valve and a valveassembly showing actuator balls in relaxed and compressed states, withthe corresponding channels open and pinched closed, respectively,according to one embodiment of the invention.

FIGS. 8C-8D illustrate the function of the normally closed valve, whichhas upper layer 831 and the lower layer 832. Concave valve channel 833was designed to match the contour of the actuator balls 834, which areheld in place by the ball cage 835. Actuator 836 rotates around its axis837 such that actuation pocket 838 is either above the ball 834, asshown in FIG. 8C, or not, as shown in FIG. 8D. When the pocket 838 isabove the ball 834, the elastomeric upper layer 831 and the lower layer832 are relaxed driven such that the channel 833 is open. When theactuator is rotated so that ball 834 is pressed into the two layers, thecollapsed channel ceiling 839 closes the valve.

In other embodiments of both pumps and valves, the channel can be on themating surface of the second layer of the device, such that the pressurefrom the roller compresses both the elastomer in the first layer and thematerial surrounding the channel in the second.

FIG. 8E is a perspective view of a circular through-plate25-channel/port valve 801, showing actuated surface, working channels833, registration/alignment protrusions 506, and interface ports 802,according to one embodiment of the invention.

FIG. 8F shows a plan view of a 25-port valve 801 with identifyingmarkings, e.g., “1”, “5” . . . , and actuator ball locations 818,according to one embodiment of the invention. FIG. 8G shows 25-portvalve chip 801 that is configured to operate as a multi-inputmulti-output manifold in which the insertion or elimination of actuatingballs allows the use of valve ports to serve as multiport connectionmanifolds. In this embodiment, fluidic chip 801 is conceptually the sameas that shown in FIG. 8E, with the exception that balls are missing fromfour locations 850. Aspiration pumps connected to output ports 861, 862,863, 864 draw fluid containing, for example, drugs from supply ports871, 872, 873, 874, through common channel 880. Input port 890 may beused to flush common channel 880 with drug-free media. Supply ports 871,872, 873, 874, 890 are activated by balls 818, which are toggled by anactuator (not shown) as discussed elsewhere in this document. Ball 818perpetually pinches off and creates the terminus of common channel 880,which is unused downstream of ball 818. One or more supply ports 871,872, 873, 874, 890 may be switched on or off, as may aspiration pumpsconnected to output ports 861, 862, 863, 864, thereby facilitating aconfigurable, valved manifold system. Whereas peristaltic pumps may actas closed valves when they are not running, all output ports 861, 862,863, 864 may be addressed independently, while supply ports 871, 872,873, 874, 890 may be addressed independently or interdependentlyaccording to means of actuation. Valved channel 890 is used to deliverdrug-free flush media. All other ports in the valve 801 are kept closedby having balls in them that are not accessed by the actuator.

Make-Before Break Valves

In some implementations of a multichannel perfusion system, it is usefulto be able to select between two different reservoirs for the supply ofthe perfusion medium and drugs to the cells in the wells, as would occurin the course of long-term perfusion of printed tissue, for example withand without growth factors or drugs or toxins.

Suppose, for example, a situation in which eight single-channel pumps orone eight-channel pump are being used deliver drugs to each of eightwells in a 24 or 96 well plate. If the media or drugs delivered to eachwell are not identical, eight RPVs would normally be used to selectwhich drug is delivered to each well. Synchronous operation of the RPPMand any normally-closed RPV would require that the pump did not applypressure to a closed channel in the RPV, requiring that the pump beturned off before a downstream valve is switched. The solution to thisis to create an open-before-close valve as illustrated by thetwo-by-eight valve illustrated conceptually in FIGS. 9A-9D. This valvecan also be described as a make-before-break (MBB) valve. The keyfeature of this valve is that the recesses 920 in the surface 910 of theactuator 916 are ovoid (FIG. 9L) rather than circles of radial lines.This enables make-before-break connections, so that the pump can remainrunning while the valve is being switched from Input A to Input Bwithout exposing the valve to the large pressure spike that would occurwhen a running pump encountered a transiently closed channel.

FIG. 9A shows schematically a valve having eight channels, Channels 1-8,where each channel has two inputs A and B and an output C, according toone embodiment of the invention.

FIGS. 9B-9D show how the switching of the actuator is accomplished bycontrolling the angle of the actuator, which has tangential ovoidactuation recesses 920 into which the balls 918 rise to create an openchannel in the normally closed RPV. The ovoid shape ensures that thereis no “off” position while switching from A to B where both inputchannels could both be closed at the same time. The eight-pole,triple-throw (A, AB, B) valve shown is designed for 16 inputs and 8outputs. Each output can include a mixture of its two inputs at the sametime, or exclusively one input or the other input, depending upon thespeed with which the valve is switched from one position to another, orheld in either A or B or midway between the two. An actuator can beoscillated or rotated to achieve multiplexing of input solutions. Withthis design, there is no need to shut off the pump duringvalve-switching operations.

FIG. 9B shows a first valve state of which the actuator is positionedsuch that only one ball (denoted by a white circle) 918 is located overthe channel of input A in the ovoid actuation recesses 920, which noforce is imposed on the channel of input A by the inner ball so as toallow a fluid flow through the channel input A, and one ball (denoted bya black circle) 918 is located over the channel of input B outside theovoid actuation recesses 920, which a force is imposed on the channel ofinput B by the outer ball so as to occlude a fluid flow through thechannel input B. Accordingly, input A is fluidically connected to outputC and input B is fluidically disconnected to output C in each of theeight channels.

FIG. 9C shows a second valve state of which the actuator is positionedsuch that two balls (denoted by a white circle) 918 are located over thechannels of inputs A and B in the ovoid actuation recesses 920, which noforce is imposed on the channel of inputs A and B by the inner balls soas to allow fluid flows through the channel inputs A and B. Accordingly,both inputs A and B are fluidically connected to output C in each of theeight channels.

FIG. 9D shows a third valve state of which the actuator is positionedsuch that only one ball (denoted by a white circle) 918 is located overthe channel of input B in the ovoid actuation recesses 920, which noforce is imposed on the channel of input B by the inner ball so as toallow a fluid flow through the channel input B, and one ball (denoted bya black circle) 918 is located over the channel of input A outside theovoid actuation recesses 920, which a force is imposed on the channel ofinput A by the outer ball so as to occlude a fluid flow through thechannel input A. Accordingly, input A is fluidically disconnected tooutput C, while input B is fluidically connected to output C in each ofthe eight channels.

Other embodiments of this approach are possible. The direction of theflow through the valve can be reversed so that a single input can bedirected either of two outputs.

FIGS. 9E-9G and FIGS. 9H-9J (photographs of the valve) illustrateequivalent positions for an eight-pole, two-throw valve using acircular, through-plate fluidic chip according to embodiments of theinvention.

FIG. 9K shows a fluidic chip support plate/structure 505 with segmentalopenings 520 and the circular, through-plate fluidic chip 901. FIG. 9Lshows the valve actuator drivehead 916 with a threaded set-screw hole949 with eight grooves 920 formed in the surface 910 of the actuatordrivehead 916, as required for operation of a normally-closed RPV. Eachof these grooves 920 is a segment of a circle as required for theopen-before-closed operation.

FIG. 10A shows a make-before break (MBB) valve 1000 by utilizing anstandard 25-port valve chip 801 (FIG. 10D) according to embodiments ofthe invention. MBB means there is no actuator position in which allports are closed. FIG. 10B shows an actuator 1016 for the MBB valve1000.

FIG. 10C shows operations of the MBB valve 1000 using one pair of portsonly by rotating the actuator 1016 at predetermined positions.Additional groups of ports may be added/valved similarly on the samechip. Always-depressed balls may be incorporated to isolate thesegroups. Valved ports do not need to be in pairs (of two)—concept may beapplied to 3 or 4 ports per group, or more depending on chip layout.

Arc shapes pictured represent pockets/depressions in actuator. Ballsthat fall into pockets result in open channels. Balls that do not fallinto pockets (actuated balls) result in closed (pinched-off) channels.Ball positions/locations, pocket shapes may be adapted for variousfunctionalities. Pockets feature gradual roll-on/-off ramps to reducetorque effects of spring-loaded balls In this mock-up, the MBB conceptis applied to an existing 25-port valve chip as shown in FIG. 10D. Thereare six individual fluidic circuits as shown in FIG. 10C, each isaccessed through that circuit's respective port group (not shown,always-depressed balls isolating the six circuits). Ports 2, 6, 10, 14,18 and 22 serve as group-specific commons. Ports 1, 5, 9, 13, 17, and 21open in unison, as do ports 3, 7, 11, 15, 19, 23. Ports 4, 8, 12, 16,20, and 24 are not used in this embodiment, but they may be used forflushing purposes in some configurations.

In other embodiments, the actuator can have different numbers of grooveswith different arc lengths.

In other embodiments, the valve chip can have more than 25 ports.

In other embodiments, the valve chip can have fewer than 25 ports.

In other embodiments, the angular spacing between the actuation pointscan be adjusted for different applications.

Ribbon Connectors

The large number of fluid-carrying tubes in many applicationscomplicates the assembly, use, and maintenance of pump-valve systems.The cartridge and through-plate fluidics approach can simplify this bythe fabrication of fluidic ribbon connectors that mate to cast-in-placeports in both the bioreactors and the pump and valve fluidic chips. FIG.11A shows one embodiment of this approach. Bioreactor 1101 needs to beconnected to valve cartridge 1102, pump cartridge 1103, and multiplereservoir cartridges 1104. This can be accomplished with ribbonconnector 1105 that has as an integral part bioreactor connector tubes1106, valve connector tubes 1107, pump tubes 1108, and reservoir tubes1109. The pattern of channels in ribbon connector 1105 determines theconnectivity of all of the various components to provide the desiredfluid from to and from the bioreactor 1101 and the four reservoirs 1104.

FIG. 11B shows how the ribbon connector 1105 can be lowered onto theother components, with each of the pin inserted into the correspondingports on each device.

FIG. 11C shows how an accessory as described above can be positionedbetween a pump or valve cartridge and a ribbon connector. Accessory 1110has connector tubes 1120 that insert into the corresponding ports oncircular fluidic chip 1111 that is held in place by fluid support plate1112. The fluidic chip 1111 is operated by actuator 1130. The ribbonconnector 1105 has connector tubes 1106 that insert into the accessory1110 to complete the fluidic pathways.

FIG. 11D shows the details of the interface between a bioreactor 1101and the ribbon connector 1105. Channels 1180 in the ribbon connectorterminate in connector ports 1185, into which are inserted connectortubes 1106. This tubes mate with the corresponding tubing ports 1116 inthe bioreactor 1101, so that fluid can flow through the tubes intobioreactor channels 1191 and into and then out of bioreactor chamber1192.

Pump-Valve (P-V) Systems: Integrated Puck—Pump System

FIG. 12A shows how the Puck neurovascular unit (NVU) bioreactor 1200 canbe merged with the through-plate fluidic with an interface fluidic 1210and enclosed motor cartridge 1230 to provide a compact means of pumpingfluid from input reservoirs 1221, through the NVU, and then to outputreservoirs 1225. Standoffs 1250 allow the device to operate inverted asmay be needed to seed certain cell types in particular NVU compartments.FIG. 12B shows slightly different embodiment where the interface fluidic1210 allows the NVU 1200 to extend beyond the motor cartridge 1230 formicroscopy. FIG. 12C shows a third embodiment where the interfacefluidic 1210 is in the form of a ribbon fluidic 1212 with integraltubing ports 1215 such that the motor cartridge 1230 is horizontal.

FIG. 13A shows the configuration of pump and valve cartridges to serveas s perfusion controller for the Nortis organ-on-chip device 1301,which is inserted into the Nortis chip holder 1302, which in turn ismounted to base 1303. Pump and valve motor cartridges 1304 are connectedto the Nortis chip by tubing 1306, and to reservoir vials 1305 by tubingthat is not shown. FIG. 13B is a rendering of the Nortis chip with itsinternal fluidic channels inserted into the holder. FIGS. 13C and 13Dshow exploded and assembled views of the Nortis chip and its holder, andthe needles, tubing, ferules, and clamps used to hold the components inplace. FIG. 13E shows how the assembly in FIG. 13B can have the tubingreplaces by a fluidic connector 1330.

FIGS. 14A-14B show a perfusion controller/NVU caddy according to oneembodiment of the invention. In this exemplary embodiment, the perfusioncontroller/NVU includes two pumps 1410, and four vials 1460 positionedat about 10° angle to assist in full uptake from the vials, which aredisposed on a platform 1401. There is a single square Petri dishposition 1470 on the platform 1401 for the NVU 1400. In certainembodiments, this is designed with an adapter for pucks and thermallyconscious layout in mind, and is all stainless steel and HDPEconstruction. Also, handles are bendable to facilitate lifting off flatsurface.

FIG. 14C shows a 24-well microformulator system according to oneembodiment of the invention. In this exemplary embodiment, the 24-wellmicroformulator system includes six motor positions 1410: 4 valves and 2pumps, which works with the enclosed motor cartridge designs. The24-well microformulator system also has six vial positions 1460, and amachined polycarbonate well plate (24 well) lid 1470 with two needlesper well, clear epoxy cast in place, intubated with Tygon of matchedlength (not shown). All these devices and components are disposed on aplatform 1401. The compact design is all stainless steel and HDPEconstruction, and handles are bendable to facilitate lifting off flatsurface.

FIG. 14D shows a 24-transwell microformulator system according to oneembodiment of the invention. In this exemplary embodiment, the24-transwell microformulator system includes twelve motor positions1410: four sets that comprise two valves and one pump; eight vialpositions 1460; and a machined polycarbonate well plate lid (e.g.,compatible with a 24-well HTS Transwell insert) 1470, with four needlesper well—two outside and two inside transwell and clear epoxy cast inplace, intubated with Tygon of matched length (not shown). Allcomponents are distributed over and attached to platform 1401. Thecompact design is all stainless steel and HDPE construction, andvertical handles decrease footprint but still easy to carry. Further,the 24-transwell microformulator is portable.

FIG. 14E shows a pharmacokinetic sampling module according to oneembodiment of the invention. In certain embodiments, the pharmacokineticsampling module is designed to deliver time-varying media to one or moreNVUs in holder 1410, and the pumps and valves are configured so as todeliver samples of the bioreactor effluent to well plate 1470 at timeintervals of user choosing. In one embodiment, the modules that aremounted to base 1401 are divided into three functional segments:pharmacokinetic (PK) drug delivery (leading to the NVU), the NVU, andsample collection into the well plate 1470. Tubing is not shown.

As disclosed above, the make-before-break valve allows for dynamicswitching between straight and drug-containing media without causingdownstream flow variation. For the PK drug delivery: fluids are drawnfrom vials through the make-before-break valve by the pump that leads tothe NVU. For the sample collection: fluids exit the NVU under their ownpressure to a pair of wells (one for the top and one for the bottomchamber of the NVU) on the well plate. This separation prevents upstreamflow disturbance. From these wells the fluids are drawn up andtransported to a large collection vial though two valves in series. Whentime comes to take a sample the flow is momentarily diverted to a samplewell.

In this exemplary embodiment shown in FIG. 14E, the pharmacokineticsampling module includes ten motor positions 1410: six valves and fourpumps, eight vial positions 1460 with each vial at 10° angle to assistin full uptake from vial, and a single square Petri dish position 1410for NVU. The pharmacokinetic sampling module is designed with an adapterfor pucks. The pharmacokinetic sampling module also includes a machinedpolycarbonate well plate (96 well) lid 1470, with one needle per well (2wells are passthrough hence have 2 needles), and clear epoxy cast inplace, intubated with Tygon of matched length. The pharmacokineticsampling module is all stainless steel and HDPE, with Bent handles tofacilitate lifting off flat surface, a thermally conscious layout. Thepharmacokinetic sampling module is also designed for multiple perincubator shelf.

FIG. 14F shows a pharmacokinetic sampling module according to oneembodiment of the invention. In certain embodiments, the pharmacokineticsampling module—the 50-port valve is designed to have identical featuresto current valve option.

In this exemplary embodiment shown in FIG. 14F, the pharmacokineticsampling module includes two fewer valves (8 motors total) 1410 byaddressing sample wells with two 50-port valves instead of four 25-portones, eight vials 1460 plus 6 Falcon tubes or other accessory, apolycarbonate lid 1470 with embedded needles. All stainless steel andHDPE design with user is in mind. Such design allows for additionalspace for Falcon tubes for long-run autonomous perfusion or otheraccessories.

The foregoing description of the exemplary embodiments of the inventionhas been presented only for the purposes of illustration and descriptionand is not intended to be exhaustive or to limit the invention to theprecise forms disclosed. Many modifications and variations are possiblein light of the above teaching.

The embodiments were chosen and described in order to explain theprinciples of the invention and their practical application so as toenable others skilled in the art to utilize the invention and variousembodiments and with various modifications as are suited to theparticular use contemplated. Alternative embodiments will becomeapparent to those skilled in the art to which the invention pertainswithout departing from its spirit and scope. Accordingly, the scope ofthe invention is defined by the appended claims rather than theforegoing description and the exemplary embodiments described therein.

1. A fluidic device, comprising: a fluidic chip comprising a body havinga first surface and an opposite, second surface, one or more channelsformed in the body in fluidic communications with input ports and outputports for transferring one or more fluids between the input ports andthe output ports, and a fluidic chip registration means formed on thefirst surface for aligning the fluidic chip with a support structure;and an actuator configured to engage with the one or more channels atthe second surface of the body for selectively and individuallytransferring the one or more fluids through the one or more channelsfrom at least one of the input ports to at least one of the output portsat desired flowrates.
 2. The fluidic device of claim 1, furthercomprising a motor to operably drive the actuator to be activated ordeactivated.
 3. The fluidic device of claim 1, wherein the body of thefluidic chip comprises a first layer and a second layer, each layerhaving a first surface and an opposite, second surface, wherein the oneor more channels are grooved on a first surface of the second layer, asecond surface of the first layer is planar and bonded to the firstsurface of the second layer to seal an open side of the one or morechannels in the first surface of the second layer, and the second layeris elastomeric, such that compression of the actuator on a secondsurface of the second layer causes at least one of the one or morechannels in the second layer to be occluded, wherein the first andsecond surfaces of the body are coincident with the first surface of thefirst layer and the second surface of the second layer, respectively. 4.The fluidic device of claim 1, wherein the fluidic chip registrationmeans is configured such that the fluid chip is allowed for multiplefluid chip orientations while maintaining automatic and precisemechanical alignment to the support structure.
 5. The fluidic device ofclaim 1, wherein the fluidic chip registration means comprises at leastone protrusion protruded the first surface of the body.
 6. The fluidicdevice of claim 5, wherein the least one protrusion is configured tofluidically communicate the one or more channels with interface portsthat allow connection of external tubing to the fluidic chip through abase plate.
 7. The fluidic device of claim 1, wherein the fluid chip isconfigured such that one or more plug-in accessories are addable in orremovable from the fluid chip, wherein the one or more plug-inaccessories comprise capacitors, adjustable fluidic resistors,electrical or electrochemical sensors, photosensors for detecting ortracking bubbles for either bubble detection or for determining flowrates, flowmeters, manifolds, overpressure relief (blow-off) valves,check valves, bubble traps, injection ports, bioreactors, or acombination of them.
 8. (canceled)
 9. The fluidic device of claim 1,wherein the fluidic chip is a circular through-plate fluidic chip. 10.(canceled)
 11. The fluidic device of claim 1, wherein the actuatorcomprises a plurality of rolling members and a driving member configuredsuch that when the driving member rotates, the plurality of rollingmembers rolls along the one or more channels so as to selectively andindividually transferring the one or more fluids through the one or morechannels at the desired flowrates.
 12. The fluidic device of claim 11,being a capacitive pump, wherein the one or more channels comprise onechannel having a middle, circumferential portion with two end portions,each end portion being coupled to a port through a chamber or a bubbletrap, wherein the chamber or bubble trap operably function as capacitorto reduce flow and pressure transients associated with the rollingmembers of the actuator rolling on or off said channel.
 13. (canceled)14. The fluidic device of claim 12, wherein the capacitor is a shuntcapacitor, or a bubble trap capacitor.
 15. The fluidic device of claim12, wherein the two chambers are identical to or different from oneanother, and are in any one of geometric shapes.
 16. The fluidic deviceof claim 12, wherein the fluidic chip further comprises a ridge formedon the second surface of the body in relation to said channel forallowing the actuator to gradually engage and disengage with saidchannel and a working fluid to prevent backflow and reducingpulsatility.
 17. The fluidic device of claim 16, wherein the ridge isramps with angles for a start and an end of the ramp formed at each endof the ridge for eliminating backflow and stopping flow as the rollingmembers enter and leave the ridge.
 18. The fluidic device of claim 9,being a rotary planar valve (RPV) comprising a multi-channel valve, amanifold valve, or a multi-throw valve.
 19. The fluidic device of claim18, wherein each of the one or more channels comprises one or moresub-channels connected to one or more input ports and one or moreoutputs, wherein all the sub-channels of the one or more channels arespaced-apart in the radial channel configuration.
 20. The fluidic deviceof claim 19, wherein the actuator comprises a cage defining a pluralityof spaced-apart openings; a plurality of pop-up members, each pop-upmember retained in a respective opening of the cage and being verticallymovable therein; and a drivehead having a surface and at least onerecess formed on the surface, wherein the cage is placed on the secondsurface of the fluidic chip to constrain each pop-up member in aposition immediately on a respective sub-channel, such that when apop-up member is pressed into the second surface of the fluidic chip, asub-channel that is immediately on the pop-up member is compressed,otherwise, said sub-channel is uncompressed; and wherein the driveheadis rotatably engaged with the cage such that as the drivehead rotates ata position, any selected pop-up members positioned in the at least onerecess arise to create open sub-channels corresponding to the selectedpop-up members, thereby selectively unoccluding or occluding fluid flowsthrough desired sub-channels.
 21. (canceled)
 22. The fluidic device ofclaim 20, wherein the at least one recess comprises a plurality oftangential ovoid recesses.
 23. The fluidic device of claim 22, whereinthe plurality of tangential ovoid recesses is configured to ensure thatthere is no “off” position for the plurality of pop-up members whileswitching from one input port to another input port where both inputsub-channels connected to said two input ports are closed at the sametime.
 24. (canceled)
 25. The fluidic device of claim 20, wherein thefluidic chip and the actuator are configured such that there areactuated balls that open and close channels upon which they reside,unactuated balls underneath which channels are always closed, and absentballs underneath which channels are always open, thereby partitioningthe valve into a plurality of independent fluid-containing regionsseparated by the unactuated balls, each region having its owninlet/outlet ports, a group of channels, and actuated balls such that bya selection of the actuated balls, flows to or from the ports withinsaid region are dynamically controllable, which allowing a plurality ofisolated fluidic circuits to exist on a single chip. 26-42. (canceled)